Jones, L.C.; (2004) Polymorphisms in nitric oxide regulatory enzymes and effects on vascular function. Doctoral thesis , University of London.

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Abstract

Nitric oxide (NO) is an important signalling molecule of the central nervous system (CNS), immune system and vascular endothelium. In the vascular system NO acts as a vasodilator as well as having anti-thrombotic and atheroprotective functions. The development of cardiovascular disease (CVD) is a complex multifactorial process known to have a heritable component. The aim of this study therefore was to investigate the role of three candidate genes involved in regulation of NO synthesis and susceptibility to CVD. This study investigated the association between cardiovascular risk factors and polymorphisms in the p22phox subunit of NADPH oxidase, GTPCH1 and DDAH2. This study showed the previously identified C242T polymorphism in p22phox was associated with endothelium-dependent vasodilation in healthy subjects. Individuals homozygous for the T allele exhibited increased endothelium-dependent vasodilation compared to C allele carriers. Single strand conformational polymorphism analysis (SSCP) identified four polymorphisms within the GCH1 gene, three in the promoter (-577G/A, -741T/C and -796G/A) and one in intron 1 (599C/G). Genotyping of 2390 healthy men revealed an association between the -796 and -577 polymorphisms and circulating levels of neopterin. An association was also found between -796 genotype and endothelial function in a second cohort of 246 healthy subjects. SSCP of the DDAH2 gene identified six polymorphisms. Five in the promoter region at position - 1415G/A, -1151C/A, -1020C/G, -871 6G/7G and -449C/G and the sixth at position 618C/T within intron 4. No significant associations were identified between DDAH2 genotype and ADMA, SDMA ADMA/SDMA ratio or other cardiovascular disease risk factors in healthy subjects, renal failure patients or diabetics. In conclusion, this study has identified common polymorphisms in enzymes affecting NO synthesis or inactivation. Polymorphisms in the p22phox gene and GTPCH1 gene were associated with risk factors for cardiovascular disease including endothelium-dependent vasodilation and plasma neopterin (a marker of BH4).

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